Mao P, Manczak M, Calkins MJ, Truong Q, Reddy TP, Reddy AP, Shirendeb U, Lo HH, Rabinovitch PS, Reddy PH. Mitochondria-targeted catalase reduces abnormal APP processing, amyloid β production and BACE1 in a mouse model of Alzheimer's disease: implications for neuroprotection and lifespan extension. Hum Mol Genet. 2012 Jul 1;21(13):2973-90. PubMed.
Recommends
Please login to recommend the paper.
Comments
University of Kansas
This paper places relationships between oxidative stress, BACE, and amyloidosis within a very interesting context. In doing so, it provides insight into AD etiology.
University of Kansas
Mitochondrial dysfunction is an early pathological event in the Alzheimer’s disease (AD) brain. Defects in brain energy metabolism and key respiratory enzyme activity, increased mitochondrial oxidative stress, and alterations in mitochondrial structure, including in the mitochondrial permeability transition pore, occur in the AD-affected regions. However, the mechanisms underlying mitochondrial damage and its association with AD pathology are poorly understood. The questions of whether and how targeting mitochondria serve as a therapeutic strategy for AD are worth addressing.
This recent study led by Hemachandra Reddy at Oregon Health and Science University supports the concept that mitochondrial oxidative stress plays a primary role in amyloid pathology and cognitive decline in AD. The researchers have extensively analyzed the protective effects of the mitochondria-targeted antioxidant catalase (MCAT) and lifespan extension in mice expressing Aβ (Tg2576 mice) from birth to death. They provide substantial evidence that increased MCAT blunts not only oxidative stress and oxidative DNA damage, but also brain Aβ accumulation. Interestingly, MCAT also interferes with APP processing and Aβ production/accumulation by a reduction in the levels of full-length APP, CTF99, BACE1, and Aβ levels, and increased levels of soluble APPα, CTF83, and the Aβ-degrading enzymes neprilysin and insulin-degrading enzyme. Consistent with published studies (Schriner et al., 2005), lifespan extends four to five months in MCAT mice and double MCAT/APP mice compared to the non-Tg and single APP mice, respectively.
These data significantly enhance our understanding of the contribution of mitochondrial reactive oxygen species to aging and AD-etiopathology. Mitochondrial oxidative stress could be an upstream modulator of amyloid pathology and APP processing, leading to impaired learning and memory in AD sufferers. Thus, mitochondria-targeted molecules, such as oxidative stressors or antioxidants, may be effective approaches for halting and preventing AD progression. Increasing antioxidants, such as catalase, at the early stage of AD might be one of the therapeutic approaches for prevention and treatment of the disease.
Previously, we demonstrated that blockade of the cyclophilin D-dependent mitochondrial permeability transition pore significantly improves mitochondrial and cognitive function through increases in mitochondrial calcium buffer capacity, respiratory function, and ATP levels, and attenuation of mitochondrial oxidative stress in Alzheimer’s disease neurons and transgenic AD mice (Du et al., 2008; Du et al., 2011). Furthermore, in AD mice overexpressing amyloid precursor protein and Aβ (J-20 line), blocking the interaction of mitochondrial Aβ with amyloid binding alcohol dehydrogenase (ABAD) suppresses the production/accumulation of reactive free radicals (ROS) in mitochondria, and, as a result, reverses abnormal mitochondrial function and improves learning and memory (Lustbader et al., 2004; Yao et al., 2011).
Taken together, these studies indicate mitochondria as a potential therapeutic target for AD, especially at the early stage of the disease before profound neuronal injury.
References:
Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, Coskun PE, Ladiges W, Wolf N, Van Remmen H, Wallace DC, Rabinovitch PS. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science. 2005 Jun 24;308(5730):1909-11. PubMed.
Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM, Yan Y, Wang C, Zhang H, Molkentin JD, Gunn-Moore FJ, Vonsattel JP, Arancio O, Chen JX, Yan SD. Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease. Nat Med. 2008 Oct;14(10):1097-105. PubMed.
Du H, Guo L, Zhang W, Rydzewska M, Yan S. Cyclophilin D deficiency improves mitochondrial function and learning/memory in aging Alzheimer disease mouse model. Neurobiol Aging. 2011 Mar;32(3):398-406. PubMed.
Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, Wang N, Caspersen C, Chen X, Pollak S, Chaney M, Trinchese F, Liu S, Gunn-Moore F, Lue LF, Walker DG, Kuppusamy P, Zewier ZL, Arancio O, Stern D, Yan SS, Wu H. ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease. Science. 2004 Apr 16;304(5669):448-52. PubMed.
Yao J, Du H, Yan S, Fang F, Wang C, Lue LF, Guo L, Chen D, Stern DM, Gunn Moore FJ, Xi Chen J, Arancio O, Yan SS. Inhibition of amyloid-beta (Abeta) peptide-binding alcohol dehydrogenase-Abeta interaction reduces Abeta accumulation and improves mitochondrial function in a mouse model of Alzheimer's disease. J Neurosci. 2011 Feb 9;31(6):2313-20. PubMed.
Make a Comment
To make a comment you must login or register.